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Tabrizian, Nakisa

University of British Columbia

The evidence emanating from therapy-induced drug resistance indicates tumors can gain adaptation by transitioning to an alternative lineage state. In prostate cancer, the widespread clinical application of androgen receptor (AR) pathway inhibitors has led to accretion of tumor relapsing with loss of AR signaling and a shift from a luminal state to an alternate program. Although different genomic and epigenomics aberrations are shown to correlate with this lineage reprogramming, the molecular and signaling mechanism orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies still needs to be fully understood. Studies have shown that receptor tyrosine kinases (RTKs) can rewire the transcriptome, promoting survival and growth in the absence of AR activity. However, which RTK feeds into lineage plasticity and de-differentiation following AR pathway inhibition is still obscure. Here a survey of RTKs identified ROR2 as the top-upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity and de-differentiation by promoting stem cell-like and neuronal networks. Mechanistically, we showed that ROR2 activates MAPK/ERK/CREB signaling pathway to facilitate the expression of the lineage commitment transcription factor ASCL1 and support lineage plasticity and treatment resistance. Collectively our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.

Text

2024-01-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87057

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/